Search

Objective We conducted a pre-post pilot trial to determine the feasibility and acceptability of a multi-component intervention (pre-clinic letter, shared decision making cards and follow-up phone call) designed to facilitate SDM in pediatric inflammatory bowel disease (IBD). Methods We recruited physicians (n = 11) caring for IBD patients and families (n = 36) expected to discuss anti-tumor necrosis treatment. We measured feasibility and acceptability of the intervention, observed SDM, perceived SDM, decision conflict, and regret. Medical records were used to assess clinical outcomes, time to decision and adherence. We compared all outcomes between the usual care and intervention study arms. Results Two out of three intervention components were feasible. Visit length increased significantly in the intervention arm. Parents and patients rated the intervention as acceptable, as did most physicians. The intervention was associated with a higher-level of observed SDM. There was no difference perceived SDM, decision conflict, regret or quality of life outcomes between arms. Physician global assessment improved over time in the intervention arm. Conclusions This pilot trial provides important guidance for developing a larger scale trial of a modified intervention. Practice implications Overall, our intervention shows promise in supporting SDM and engaging both parents and patients in pediatric IBD decisions.

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Summary An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.

While fecal calprotectin (FC) is used to assess disease activity in ulcerative colitis (UC) there are little data concerning the role of serial FC levels at diagnosis in predicting clinical course. We sought to determine whether FC at diagnosis or early change following therapy predicts clinical outcomes in pediatric UC.Methods: Children with newly diagnosed UC were treated with standardized regimens of mesalamine or corticosteroids (CS). CS tapering and escalation to additional therapy or colectomy were by protocol. Patients with baseline or week 4 or week 12 FC levels were included in the analysis. Our primary outcome was CS-free remission on mesalamine at week 52. We compared the prognostic value of a baseline FC as well as a change in FC by week 4 or week 12 in predicting clinical outcomes.The study included 352 children (113 initial mesalamine, 239 initial CS, mean age 12.6 years) with UC. At Week 52, 135 (38.3%), 84 (23.8%), and 19 (5.4%) children achieved CS-free remission, needed anti-tumor necrosis factor therapy or had colectomy respectively. Baseline FC was not associated with CS-free remission at week 52. However, both week 4 (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.901.00) and week 12 FC levels (OR 0.91, 95% CI 0.87-0.96) were associated with outcomes, with the latter having a stronger association with CS-free remission. Patients with a75% decrease by 12 weeks, had a 3-fold increased likelihood of CS-free remission at 1 year.Longitudinal changes in FC may predict 1 year outcomes better than values at diagnosis in children with a new diagnosis of UC.

In the United States, transgender women are disproportionately affected by HIV. However, few evidence-based prevention interventions exist for this key population. We describe two promising, locally developed interventions that are currently being implemented and evaluated through the Centers for Disease Control and Prevention Combination HIV Prevention for Transgender Women Project: (a) ChiCAS, designed to promote the uptake of pre-exposure prophylaxis (PrEP), condom use, and medically supervised hormone therapy among Spanish-speaking transgender Latinas, and (b) TransLife Care, designed to address the structural drivers of HIV risk through access to housing, employment, legal services, and medical services, including HIV preventive care (e.g., PrEP use) among racially/ethnically diverse urban transgender women. If the evaluation trials determine that these interventions are effective, they will be among the first such interventions for use with transgender women incorporating PrEP, thereby contributing to the evidence-based resources that may be used to reduce HIV risk among this population.

Background Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC). Methods This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used. Results Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]). Conclusions A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.

This article considers the depiction of the marine world and its mythical inhabitants in the Natural History of Pliny the Elder. Through an ecocritical reading of the text, whereby I consider Pliny...

Background Specific details about cardiovascular complications, especially arrhythmias, related to the coronavirus disease of 2019 (COVID‐19) are not well described. Objective We sought to evaluate the incidence and predictive factors of cardiovascular complications and new‐onset arrhythmias in Black and White hospitalized COVID‐19 patients and determine the impact of new‐onset arrhythmia on outcomes. Methods We collected and analyzed baseline demographic and clinical data from COVID‐19 patients hospitalized at the Tulane Medical Center in New Orleans, Louisiana, between March 1 and May 1, 2020. Results Among 310 hospitalized COVID‐19 patients, the mean age was 61.4 ± 16.5 years, with 58,7% females, and 67% Black patients. Black patients were more likely to be younger, have diabetes and obesity. The incidence of cardiac complications was 20%, with 9% of patients having new‐onset arrhythmia. There was no significant difference in cardiovascular outcomes between Black and White patients. A multivariate analysis determined age ≥60 years to be a predictor of new‐onset arrhythmia (OR = 7.36, 95% CI [1.95;27.76], p = .003). D‐dimer levels positively correlated with cardiac and new‐onset arrhythmic event. New onset atrial arrhythmias predicted in‐hospital mortality (OR = 2.99 95% CI [1.35;6.63], p = .007), a longer intensive care unit length of stay (mean of 6.14 days, 95% CI [2.51;9.77], p = .001) and mechanical ventilation duration(mean of 9.08 days, 95% CI [3.75;14.40], p = .001). Conclusion Our results indicate that new onset atrial arrhythmias are commonly encountered in COVID‐19 patients and can predict in‐hospital mortality. Early elevation in D‐dimer in COVID‐19 patients is a significant predictor of new onset arrhythmias. Our finding suggest continuous rhythm monitoring should be adopted in this patient population during hospitalization to better risk stratify hospitalized patients and prompt earlier intervention.

Objective Accurate and robust quality measurement is critical to the future of value-based care. Having incomplete information when calculating quality measures can cause inaccuracies in reported patient outcomes. This research examines how quality calculations vary when using data from an individual electronic health record (EHR) and longitudinal data from a health information exchange (HIE) operating as a multisource registry for quality measurement. Materials and Methods Data were sampled from 53 healthcare organizations in 2018. Organizations represented both ambulatory care practices and health systems participating in the state of Kansas HIE. Fourteen ambulatory quality measures for 5300 patients were calculated using the data from an individual EHR source and contrasted to calculations when HIE data were added to locally recorded data. Results A total of 79% of patients received care at more than 1 facility during the 2018 calendar year. A total of 12 994 applicable quality measure calculations were compared using data from the originating organization vs longitudinal data from the HIE. A total of 15% of all quality measure calculations changed (P Discussion These results demonstrate that quality measures calculated using single-site EHR data may be limited by incomplete information. Effective data sharing significantly changes quality calculations, which affect healthcare payments, patient safety, and care quality. Conclusions Federal, state, and commercial programs that use quality measurement as part of reimbursement could promote more accurate and representative quality measurement through methods that increase clinical data sharing.

The extent of SARS-CoV-2 infection throughout the United States population is currently unknown. High quality serology is a key tool to understanding the spread of infection, immunity against the virus, and correlates of protection. Limited validation and testing of serology assays used for serosurveys can lead to unreliable or misleading data, and clinical testing using such unvalidated assays can lead to medically costly diagnostic errors and improperly informed public health decisions. Estimating prevalence and clinical decision making is highly dependent on specificity. Here, we present an optimized ELISA-based serology protocol from antigen production to data analysis. This protocol defines thresholds for IgG and IgM for determination of seropositivity with estimated specificity well above 99%. Validation was performed using both traditionally collected serum and dried blood on mail-in blood sampling kits, using archival (pre-2019) negative controls and known PCR-diagnosed positive patient controls. Minimal cross-reactivity was observed for the spike proteins of MERS, SARS1, OC43 and HKU1 viruses and no cross reactivity was observed with anti-influenza A H1N1 HAI titer during validation. This strategy is highly specific and is designed to provide good estimates of seroprevalence of SARS-CoV-2 seropositivity in a population, providing specific and reliable data from serosurveys and clinical testing which can be used to better evaluate and understand SARS-CoV-2 immunity and correlates of protection.

Objective To evaluate the pharmacokinetics of tenofovir alafenamide (TAF) 10 mg with cobicistat and 25 mg without boosting in pregnant and postpartum women with HIV and to characterize TAF placental transfer and infant washout pharmacokinetics. Design Open-label, multicenter phase IV prospective study of TAF pharmacokinetics during pregnancy, postpartum, delivery, and infant washout. Methods Pregnant women receiving TAF 10 mg with cobicistat or TAF 25 mg without boosting as part of clinical care had intensive pharmacokinetic assessments performed during the second and third trimesters, and 6-12 weeks postpartum. Maternal and cord blood samples were collected at delivery, and washout pharmacokinetic samples were collected in infants. TAF concentrations were quantified using liquid chromatography/mass spectrometry. Comparisons between pregnancy and postpartum were made using geometric mean ratios (90% confidence intervals) and Wilcoxon signed-rank tests. Results Thirty-one pregnant women receiving TAF 10 mg with cobicistat-boosting and 27 women receiving TAF 25 mg without boosting were enrolled. TAF exposures did not significantly differ between pregnancy and postpartum when administered as 10 mg with cobicistat. Antepartum TAF exposures with the 25 mg dose were 33-43% lower in comparison with postpartum, but comparable with those measured in nonpregnant adults. TAF was below the lower limit of quantitation in 43 of 44 cord blood, 41 of 45 maternal blood at delivery, and all infant washout samples. Conclusion TAF exposures were comparable or higher than those measured in nonpregnant adults during pregnancy and postpartum. These findings provide reassurance on adequate TAF exposures during pregnancy, and support efforts to expand the use of TAF in pregnant women with HIV.

This study examined correlates of work-life balance perceptions for faculty from various marital/relationship and family statuses, using data from the multi-institutional survey of faculty from the Collaborative on Academic Careers in Higher Education (COACHE) project at Harvard University’s Graduate School of Education. Indicating lower work-life balance among single (rather than married/partnered) faculty, our findings call for colleges and universities to directly address the work-life struggles of single faculty members with and without children. Our findings also underscore the central importance of institutional support for making personal/family obligations and an academic career compatible for all faculty, supports that are correlated with better faculty work-life balance at the level of both individual faculty and the institution. In addition, we argue that institutional supports are particularly important for early-career faculty, who assessed their work-life balance consistently lower than faculty at higher ranks.

Introduction Gleevec, Imatinib mesylate, is the first in class BCR-ABL tyrosine kinase inhibitor initially approved to treat CML. In February 2016, generic imatinib products became available. As generic products are not required to offer comparative efficacy and safety data, differences may arise. Small reports have found no significant differences in response durability and tolerability in patients transitioned from Gleevec to generic imatinib. Further, lower cost of generic products often influence treatment decisions and patient compliance. We sought to evaluate response durability, tolerability, financial costs, and adherence in patients with chronic phase CML (cpCML) who switched from Gleevec to generic imatinib and newly diagnosed cpCML patients initiated on generic imatinib. Methods We conducted a single-center, retrospective chart review of adult patients who received imatinib therapy for cpCML between June 1, 2015 to November 14, 2019. Patients who received ≥6 months of brand through the Specialty Pharmacy Service (SPS) at Atrium Health prior to switching to generic were included in Group 1 (Switch). Patients who initiated therapy with generic imatinib dispensed from SPS were included in Group 2 (New Start). Durability of response was described determined via peripheral blood BCR-ABL transcripts by PCR and reported major molecular response (MMR) after 12 months generic imatinib therapy. Additional factors characterizing the durability and tolerability of therapy included adverse effects due to drug, dose modifications, adherence rate, prescription cost per month, and frequency of switch between generic products. Results Of 298 patients assessed, 12 patients were evaluable. There were 7 Switch patients and 5 New Start patients. Figure 1. All 12 patients met WHO diagnostic cpCML criteria. No patients in either group had accelerated or blast phase CML, no patients received maintenance imatinib following allogeneic HCT. In the Switch Group, 4 patients (57%) achieved MMR after 12 months of generic therapy. Of the 3 patients that did not achieve MMR, 1 patient relocated prior to 12-month assessment, 1 patient was noted to be non-compliant, and 1 patient had several treatment delays and dose reductions due to toxicities. 1 New Start patient achieved MMR at 12 months. Of those not achieving MMR, 1 was started on a reduced dose (100 mg /day) due to renal dysfunction, 1 had a PDC of 49.10% due to treatment delays while receiving treatment for a different malignancy, and 2 patients had logarithmic decreases in BCR-ABL but had not crossed the MMR threshold after 12 months of therapy. 5 Switch patients (71.4%) reported at least 1 adverse effect related to therapy, 3 of these (42.9%) required dose reduction. The adverse effects requiring dose reductions in the New Start patients included thrombocytopenia (n=2) and myalgia (n=1). All New Start patients reported at least 1 adverse effect with none of these patients requiring a dose reduction. Cost stayed the same or was reduced for 85.7% of the Switch patients, 1 patient experienced a cost increase and did not have co-pay assistance, and 2 patients received copay assistance. Cost of generic therapy was 90% after 12 months on generic therapy for 71.4% Switch patients and 80% New Start patients. Table 1. and Table 2. Conclusion Patients with cpCML switched from brand to generic imatinib and patients newly started on generic imatinib appear to have durable responses and tolerance to generic imatinib. Dose reductions and non-adherence may have contributed to inadequate disease control in patients not achieving MMR in both groups. Patients switched from brand to generic imatinib may develop new side effects necessitating dose reduction. Thrombocytopenia may be more common in patients switched from brand to generic imatinib. Adherence to brand and generic imatinib is high and medication is affordable with most patients paying Disclosures Knight: Foundation for Financial Planning: Research Funding. Ai:Celgene: Speakers Bureau; Incyte: Speakers Bureau. Grunwald:Premier: Consultancy; Astellas: Consultancy; Janssen: Research Funding; Merck: Research Funding; Janssen: Research Funding; Forma Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Astellas: Consultancy; Premier: Consultancy; Trovagene: Consultancy; Trovagene: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Merck: Consultancy; Merck: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Cardinal Health: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Cardinal Health: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Genentech/Roche: Research Funding; Premier: Consultancy; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding; Forma Therapeutics: Research Funding. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees; Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia. Copelan:Amgen: Membership on an entity's Board of Directors or advisory committees. Chojecki:Novartis: Other: Investigator Meeting Attendance; Incyte: Research Funding.

Exposure to air pollutants such as ozone (O3) is associated with adverse pregnancy outcomes, including higher incidence of gestational hypertension, preeclampsia, and peripartum cardiomyopathy; however, the underlying mechanisms of this association remain unclear. We hypothesized that O3 exposures during early placental formation would lead to more adverse cardiovascular effects at term for exposed dams, as compared with late-term exposures. Pregnant Sprague Dawley rats were exposed (4 h) to either filtered air (FA) or O3 (0.3 or 1.0 ppm) at either gestational day (GD)10 or GD20, with longitudinal functional assessments and molecular endpoints conducted at term. Exposure at GD10 led to placental transcriptional changes at term that were consistent with markers in human preeclampsia, including reduced mmp10 and increased cd36, fzd1, and col1a1. O3 exposure, at both early and late gestation, induced a significant increase in maternal circulating soluble FMS-like tyrosine kinase-1 (sFlt-1), a known driver of preeclampsia. Otherwise, exposure to 0.3 ppm O3 at GD10 led to several late-stage cardiovascular outcomes in dams that were not evident in GD20-exposed dams, including elevated uterine artery resistance index and reduced cardiac output and stroke volume. GD10 O3 exposure proteomic profile in maternal hearts characterized by a reduction in proteins with essential roles in metabolism and mitochondrial function, whereas phosphoproteomic changes were consistent with pathways involved in cardiomyopathic responses. Thus, the developing placenta is an indirect target of inhaled O3 and systemic maternal cardiovascular abnormalities may be induced by O3 exposure at a specific window of gestation.

In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy (P 23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma‐glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for MMP7 (r = 0.70; P

Objective Coronavirus disease 2019 (COVID-19) has disproportionately impacted the African American community. This study aims to identify the risk factors for severe COVID-19 disease in African American patients. Methods This was a retrospective cross-sectional analysis of African American patients with COVID-19 treated between March 12 and April 9, 2020, at a single tertiary center. The primary outcome of interest was severe disease defined as those requiring intensive care unit (ICU) admission. Results The study included 158 consecutive patients. The mean age was 57 years, and 61% were women. The mean (SD) of BMI was 33.2 (8.6) kg/m2 . Overall, patients admitted to the ICU were older (62 vs. 55 years, P = 0.003) and had higher BMI (36.5 kg/m2 vs. 31.9 kg/m2 , P = 0.002). In unadjusted and adjusted analysis, the factors most associated with ICU admission in this sample were age (adjusted odds ratio [aOR]: 1.073; 95% CI: 1.033-1.114), BMI (aOR: 1.115; 95% CI: 1.052-1.182), and lung disease (aOR: 3.097; 95% CI: 1.137-8.437). Conclusions This study identified risk factors for severe disease in COVID-19, specifically in an African American population. Further inclusive research aimed at optimizing clinical care relevant to the African American population is critical to ensure an equitable response to COVID-19.

OBJECTIVE Coronavirus disease 2019 (COVID-19) mortality is high in patients with hypertension, obesity, and diabetes. We examined the association between hypertension, obesity, and diabetes, individually and clustered as metabolic syndrome (MetS), and COVID-19 outcomes in patients hospitalized in New Orleans during the peak of the outbreak. RESEARCH DESIGN AND METHODS Data were collected from 287 consecutive patients with COVID-19 hospitalized at two hospitals in New Orleans, LA, from 30 March to 5 April 2020. MetS was identified per World Health Organization criteria. RESULTS Among 287 patients (mean age 61.5 years; female, 56.8%; non-Hispanic Black, 85.4%), MetS was present in 188 (66%). MetS was significantly associated with mortality (adjusted odds ratio [aOR] 3.42 [95% CI 1.52–7.69]), intensive care unit requirement (ICU) (aOR 4.59 [CI 2.53–8.32]), invasive mechanical ventilation (IMV) (aOR 4.71 [95% CI 2.50–8.87]), and acute respiratory distress syndrome (ARDS) (aOR 4.70 [95% CI 2.25–9.82]) compared with non-MetS. Multivariable analyses of hypertension, obesity, and diabetes individually showed no association with mortality. Obesity was associated with ICU (aOR 2.18 [95% CI 1.25–3.81]), ARDS (aOR 2.44 [95% CI 1.28–4.65]), and IMV (aOR 2.36 [95% CI 1.33–4.21]). Diabetes was associated with ICU (aOR 2.22 [95% CI 1.24–3.98]) and IMV (aOR 2.12 [95% CI 1.16–3.89]). Hypertension was not significantly associated with any outcome. Inflammatory biomarkers associated with MetS, CRP and lactate dehydrogenase (LDH), were associated with mortality (CRP [aOR 3.66] [95% CI 1.22–10.97] and LDH [aOR 3.49] [95% CI 1.78–6.83]). CONCLUSIONS In predominantly Black patients hospitalized for COVID-19, the clustering of hypertension, obesity, and diabetes as MetS increased the odds of mortality compared with these comorbidities individually.

Pharmacological interactions limit treatment options for children living with human immunodeficiency virus (HIV) and tuberculosis (TB). We found that 12 mg/kg twice daily raltegravir chewable tablets (administered after crushing) safely achieved pharmacokinetic targets in children living with HIV aged 4 weeks to Clinical Trials Registration NCT01751568.

Background Reports on the feasibility and effectiveness of translating proactive, antitumor necrosis factor (TNF) therapeutic drug monitoring (TDM) for inflammatory bowel disease into practice-wide quality improvement (QI) are lacking. We aimed to determine whether a TDM QI program improved outcomes at a large academic pediatric gastroenterology practice. Methods We instituted local anti-TNF TDM practice guidelines to proactively monitor and optimize drug levels (goal >5 μg/mL). We conducted a retrospective single-center cohort analysis of patient outcomes before (pre-TDM) and after (post-TDM) guideline institution and assessed the independent effect by multivariable regression. Primary outcome was sustained clinical remission (SCR22-52), defined as physician global assessment (PGA) of inactive from 22 to 52 weeks and off corticosteroids at 52 weeks. Results We identified 108 pre-TDM and 206 post-TDM patients. The SCR22-52 was achieved in 42% of pre-TDM and 59% of post-TDM patients (risk difference, 17.6%; 95% CI, 5.4–29%; P = 0.004). The post-TDM group had an increased adjusted odds of achieving SCR22-52 (odds ratio, 2.03; 95% CI, 1.27–3.26; P = 0.003). The adjusted risk of developing high titer antidrug antibodies (ADAs) was lower in the post-TDM group (hazard ratio, 0.18; 95% CI, 0.09–0.35; P < 0.001). Although the risk of anti-TNF cessation for any reason was not significantly different, there was a lower adjusted risk of cessation related to any detectable ADA in the post-TDM group (hazard ratio, 0.45; 95% CI, 0.26–0.77; P = 0.003). Conclusions A practice-wide proactive anti-TNF TDM QI program improved key clinical outcomes at our institution, including sustained clinical remission, incidence of high titer ADA, and anti-TNF cessation related to ADA.

Measuring medication adherence in pediatric inflammatory bowel diseases (IBD) is challenging because of complexities in personalized treatment regimens and increased use of biologic mono- and combination therapy. Objective measurement of adherence via electronic monitoring is the gold standard; however, it is not useful for daily monitoring when multiple medication formulations (eg, pills, injections, infusions) as well as vitamins/supplements are prescribed. Although validated subjective measures are available, they are not designed for daily use and do not capture day-to-day variation in adherence. In the following article, a new approach to measuring adherence regardless of a patient’s specific medication regimen is presented. Utilizing a micro-longitudinal design, 30 days of daily self-reported medication adherence data was collected from youth with IBD via text message. Results reflect mean adherence rates from studies utilizing pill counts and electronic monitoring, suggesting promise for the use of self-reported daily diaries to assess medication adherence in pediatric IBD.

Introduction Studies of target organs at the time of acute graft versus host disease (GVHD) are needed to identify novel inflammatory and regulatory pathways. Methods We performed a prospective transcriptome analysis of gastrointestinal (GI) biopsies at diagnosis of acute GI GVHD and compared these to bone marrow transplant (BMT) patients without GVHD. Allogeneic BMT patients ≥2 years old undergoing endoscopy for clinical indications had 2 additional rectosigmoid mucosal biopsies for transcriptome analysis. Transcriptome data from 211 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GVHD and UC. Rectal biopsies from 20 children without inflammatory bowel disease (IBD) served as controls. Results Twenty-one patients underwent endoscopy pre (n=5) or post BMT (n=16). Median age of patients was 13.5 years (range 4.5 -25 years). Four patients were excluded from analyses (pre BMT colitis n=3, no lower GI biopsy n=1). Nine patients had acute GI GVHD, while 8 patients did not (Table 1). Principal component analysis shows patient clustering of those with and without GVHD, suggesting distinct transcriptomic mechanisms driving disease (Figure 1A). We identified 1310 significant genes, 144 of which were downregulated and 1266 upregulated in acute GVHD compared to no GVHD (Figure 1B). Top upregulated biological processes in GVHD revealed an innate antimicrobial response and associated cytokine signaling, notable for interferons. Top 20 differentially expressed genes in acute GVHD (Table 2), include CXCL9, CXCL10 and CXCL11, which are chemokines involved in GVHD, and IDO1 which regulates tryptophan metabolism. Four hundred and ninety shared genes were upregulated, and 126 genes were downregulated in GVHD and UC. Notable shared downregulated pathways involved butyrate metabolism (Table 3). DUOXA2, a gene involved in regulating innate antimicrobial responses in IBD, was the top upregulated genes in pediatric IBD and was the second highest differentially expressed gene in the acute GVHD, providing additional rationale for intestinal microbiome modulation in both diseases. Genes involving the ERK1/2 cascade (Table 4) were upregulated in acute GVHD (p=1.67 × 10 −3) providing rationale for exploring ERK1/2 inhibition as novel acute GVHD treatment. Conclusions Acute GI GVHD has a distinct transcriptome signature which includes pathways of innate antimicrobial responses highlighting the role for microbiome modulation. The ERK1/2 cascade pathway is upregulated, suggesting a novel target in acute GI GVHD. Acute GI GVHD has important similarities with the UC transcriptome, including upregulation of DUOXA2 and downregulation in butyrate metabolism in both.

BackgroundThis study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples.SettingA nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children.MethodsIntensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons.ResultsA total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0-24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0-24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 μg/mL (0.16-0.28) in the second trimester, 0.21 μg/mL (0.11-0.56) in the third trimester, and 0.61 μg/mL (0.42-1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited.ConclusionsStandard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.

BackgroundMany patients in sub-Saharan Africa whom a diagnosis of tuberculosis is considered are subsequently not diagnosed with tuberculosis. The proportion of patients this represents, and their alternative diagnoses, have not previously been systematically reviewed.MethodsWe searched four databases from inception to April 27, 2020, without language restrictions (PROSPERO: CRD42018100004). We included all adult pulmonary tuberculosis diagnostic studies from sub-Saharan Africa, excluding case series and inpatient studies. We extracted the proportion of patients with presumed tuberculosis subsequently not diagnosed with tuberculosis and any alternative diagnoses received. We conducted a random-effects meta-analysis to obtain pooled estimates stratified by passive and active case finding.ResultsOur search identified 1799 studies, of which 18 studies with 14527 participants from 10 African countries were included. The proportion of patients with presumed tuberculosis subsequently not diagnosed with tuberculosis was 48.5% (95% CI 38.4-56.7) in passive and 92.7% (95% CI 83.1-97.0) in active case finding studies. This proportion increased with declining numbers of clinically diagnosed tuberculosis cases. Past history of tuberculosis was documented in only 55% of studies, with just five out of 18 reporting any alternative diagnoses.DiscussionNearly half of all patients with presumed tuberculosis in sub-Saharan Africa do not have a final diagnosis of active tuberculosis. This proportion may be higher when active case finding strategies are used. Little is known about the healthcare needs of these patients. Research is required to better characterise these patient populations and plan health system solutions that meet their needs.FundingNIHR, UK MRC

Background Burnout is an occupational syndrome that leads to mental health problems, job turnover, and patient safety events. Those caring for critically ill patients are especially susceptible due to high patient mortality, long hours, and regular encounters with trauma and ethical issues. Interventions to prevent burnout in this population are needed. Preliminary studies suggest debriefing sessions may reduce burnout. This study aims to assess whether participation in regular debriefing can prevent burnout in intensive care unit (ICU) clinicians. Methods A randomized controlled trial will be conducted in two large academic medical centers. Two hundred ICU clinicians will be recruited with target enrollment of 100 physicians and 100 non-physicians (nurses, pharmacists, therapists). Participants must have worked in the ICU for the equivalent of at least 1 full time work week in the preceding 4 weeks. Enrolled subjects will be randomized to virtually attend biweekly debriefing sessions facilitated by a psychotherapist for 3 months or to a control arm without sessions. Our debriefs are modeled after Death Cafés, which are informal discussions focusing on death, dying, loss, grief, and illness. These sessions allow for reflection on distressing events and offer community and collaboration among hospital employees outside of work. The primary outcome is clinician burnout as measured by the Maslach Burnout Inventory (MBI) Score. Secondary outcomes include depression and anxiety, as measured by the Patient Health Questionnaire 8 (PHQ-8) and Generalized Anxiety Disorder 7-item scale (GAD-7), respectively. Questionnaires will be administered prior to the intervention, at 1 month, at 3 months, and at 6 months after enrollment. These values will be compared between groups temporally. Qualitative feedback will also be collected and analyzed. Discussion With ICU clinician burnout rates exceeding 50%, Death Café debriefing sessions may prove to be an effective tool to avert this debilitating syndrome. With COVID-19 limiting social interactions and overloading ICUs worldwide, the virtual administration of the Death Café for ICU clinicians provides an innovative strategy to potentially mitigate burnout in this vulnerable population. Trial registration ClinicalTrials.gov NCT04347811. Registered on 15 April 2020

Environmental Enteric Dysfunction (EED) is a chronic inflammatory condition of the intestine characterized by villus blunting, compromised intestinal barrier function, and reduced nutrient absorption. Here, we show that key genotypic and phenotypic features of EED-associated intestinal injury can be reconstituted in a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by organoid-derived intestinal epithelial cells from EED patients and cultured in niacinamide- and tryptophan-deficient (-N/-T) medium. Exposure of EED Intestine Chips to -N/-T deficiencies resulted in transcriptional changes similar to those seen in clinical EED patient samples including congruent changes in six of the top ten upregulated genes. Exposure of EED Intestine Chips or chips lined by healthy intestinal epithelium (healthy Intestine Chips) to -N/-T medium resulted in severe villus blunting and barrier dysfunction, as well as impairment of fatty acid uptake and amino acid transport. EED Intestine Chips exhibited reduced secretion of cytokines at baseline, but their production was significantly upregulated compared to healthy Intestine Chips when exposed to -N/-T deficiencies. The human Intestine Chip model of EED-associated intestinal injury may be useful for analyzing the molecular, genetic, and nutritional basis of this disease and can serve as a preclinical model for testing potential EED therapeutics.

Objective Children with functional abdominal pain disorders (FAPD) and clinical elevations in three risk areas (anxiety, functional disability, and pain) have been found to be at increased risk for persistent disability. We evaluated if the presence of these three risk factors corresponded with greater gastrointestinal inflammation (measured via fecal calprotectin; FC) compared to those with no risk factors. FC concentration differences between children with three risk factors and those with one and two risk factors were explored. Results Fifty-six children with FAPD (Mage = 12.23) completed measures of anxiety (Screen for Child Anxiety Related Disorders), disability (Functional Disability Inventory), and pain intensity (Numeric Rating Scale). Participants were stratified into risk groups (range: 0–3). Fisher’s exact tests were conducted to determine if children with three versus fewer risk factors were more likely to have elevated FC (≥ 50 µg/g) versus normal levels. Children with three risk factors (MFC = 86.04) were more likely to have elevated FC compared to children with zero (MFC = 25.78), one (MFC = 38.59), and two risk factors (MFC = 45.06; p’s

Environmental enteropathy (EE) contributes to growth failure in millions of children worldwide, but its relationship to clinical malnutrition has not been elucidated. We used RNA sequencing to compare duodenal biopsies from adults and children with EE, and from children with severe acute malnutrition (SAM), to define key features of these malnutrition-related enteropathies.RNA was extracted and sequenced from biopsies of children with SAM in hospital (n=27), children with non-responsive stunting in the community (n=30), and adults living in the same community (n=37) using an identical sequencing and analysis pipeline. Two biopsies each were profiled and differentially expressed genes (DEGs) were computed from the comparisons of the three groups. DEG lists from these comparisons were then subjected to analysis with CompBio software to assemble a holistic view of the biological landscape and IPA software to interrogate canonical pathways.Dysregulation was identified in goblet cell/mucin production and xenobiotic metabolism/detoxification for both cohorts of children, versus adults. Within the SAM cohort, substantially greater induction of immune response and barrier function, including NADPH oxidases was noted, concordant with broadly reduced expression of genes associated with the brush border and intestinal structure/transport/absorption. Interestingly, down regulation of genes associated with the hypothalamic-pituitary-adrenal axis was selectively observed within the cohort of children with stunting.Gene expression profiles in environmental enteropathy and severe acute malnutrition have similarities, but SAM has several distinct transcriptional features. The intestinal capacity to metabolise drugs and toxins in malnourished children requires further study.BillMelinda Gates Foundation (OPP1066118).

Purpose The aim of this study is to further examine the associations of race, socioeconomic factors, and comorbidity with COVID-19 health outcomes. Methods This is a retrospective cohort study of 309 PCR confirmed COVID-19 positive adults who presented to Tulane Medical Center in New Orleans, LA, from March 9 to May 29, 2020. The primary outcomes investigated were need for invasive mechanical ventilation (IMV) and in-hospital mortality. A multivariate analysis was performed to determine socioeconomic and medical risk factors for IMV and in-hospital mortality. Results Compared to white patients, Black patients were more likely to present younger, female, obese, unemployed, and underinsured. However, when controlled for common risk factors, Black and white patients had similar risk for IMV and mortality. Increased age (≥65 years), obesity, and increased comorbidity were associated with increased risk for IMV and mortality. Conclusions Race and socioeconomic factors may increase risk for COVID-19 infection but did not affect health outcomes within the hospital setting. Therefore, the higher rates of COVID-19 infection and mortality in vulnerable populations may be better explained by lower socioeconomic status, with subsequent higher comorbidity, in these populations. Community health initiatives should be prioritized in response to the COVID-19 pandemic.

Supplemental Digital Content is available in the text., IMPORTANCE: Even with its proclivity for older age, coronavirus disease 2019 has been shown to affect all age groups. However, there remains a lack of research focused primarily on the young adult population. OBJECTIVES: To describe the epidemiology and outcomes of coronavirus disease 2019 and identify the risk factors associated with critical illness and mortality in hospitalized young adults. DESIGN, SETTINGS, AND PARTICIPANTS: A retrospective cohort study of the Society of Critical Care Medicine’s Viral Infection and Respiratory Illness Universal Study registry. Patients 18–40 years old, hospitalized from coronavirus disease 2019 from March 2020 to April 2021, were included in the analysis. MAIN OUTCOMES AND MEASURES: Critical illness was defined as a composite of mortality and 21 predefined interventions and complications. Multivariable logistic regression was used to assess associations with critical illness and mortality. RESULTS: Data from 4,005 patients (152 centers, 19 countries, 18.6% non-U.S. patients) were analyzed. The median age was 32 years (interquartile range, 27–37 yr); 51% were female, 29.4% Hispanic, and 42.9% had obesity. Most patients (63.2%) had comorbidities, the most common being hypertension (14.5%) and diabetes (13.7%). Hospital and ICU mortality were 3.2% (129/4,005) and 8.3% (109/1,313), respectively. Critical illness occurred in 25% (n = 996), and 34.3% (n = 1,376) were admitted to the ICU. Older age (p = 0.03), male sex (adjusted odds ratio, 1.83 [95% CI, 1.2–2.6]), and obesity (adjusted odds ratio, 1.6 [95% CI, 1.1–2.4]) were associated with hospital mortality. In addition to the above factors, the presence of any comorbidity was associated with critical illness from coronavirus disease 2019. Multiple sensitivity analyses, including analysis with U.S. patients only and patients admitted to high-volume sites, showed similar risk factors. CONCLUSIONS: Among hospitalized young adults, obese males with comorbidities are at higher risk of developing critical illness or dying from coronavirus disease 2019.

Introduction Tumors of the ovary and appendix have been well documented in the setting of pseudomyxoma peritonei (PMP) with constant debate over tumor origin. Generally, these tumors are found to have a single primary origin, most commonly the appendix, with metastatic spread to the ovaries. Care presentation Here we present a 61-year-old female who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) for a primary mucinous ovarian carcinoma. She presented to our institution one year later with abdominal pain and a palpable right lower quadrant mass, which on histopathologic exam was found to be a primary low grade mucinous appendiceal neoplasm (LAMN), alluding to the potential of two separate primary disease processes. Discussion/conclusion With two primary, non-synchronous lesions, a thorough literature review suggests that during the patient's initial TAH-BSO, she could have additionally undergone an appendectomy. In doing so, this would provide accurate, complete staging and determine if the two neoplasms were truly primary in origin or metastatic. In addition, new genetic markers are being discovered, such as the Special AT-rich sequence-binding protein 2 (SATB2) marker, which has been found to be positive in those with a LAMN and negative in those with a primary mucinous ovarian carcinoma. By acquiring appropriate and complete staging we can better diagnose and treat these neoplasms.

This study built upon research examining the effects of diversity in STEM (science, technology, engineering, and mathematics) fields and higher education by investigating the relationship between student perceptions of campus diversity and classroom engagement for first- and second-year Latinx and White students at two structurally diverse institutions. Findings suggested that perceptions of campus climate have a positive and significant relationship with classroom engagement—which is an important indicator of overall grade point average.

Objectives:Drug–drug interactions limit current antiretroviral treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and well tolerated dose

OBJECTIVES: Among adolescents with inflammatory bowel disease (IBD), nonadherence rates are 50 to 88% across medications. Improving education in adults with IBD has been shown to improve coping and adherence to treatment in adults with IBD. Therapeutic patient education (TPE) has been used in patients with chronic diseases to train patients in skills to support treatment adaptation and condition management. This study tested the feasibility and preliminary efficacy of a novel TPE intervention in adolescents with IBD. METHODS: In this pilot, mixed-methods study, we evaluated the feasibility and preliminary efficacy of TPE with the IBD Pocket Guide on medication adherence, IBD knowledge, and transition readiness in adolescents ages 11 to 18 years. Medication adherence was monitored using a MedMinder Pill Dispensing system. Participants who were

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

Background & aimsThere are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2).MethodsWe selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal-Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups.ResultsThe median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P= .01). Median baseline plasma concentrations of COMPdid not differ significantly among groups. A model comprising baseline concentrations ofCOL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of0.80 (95% CI, 0.71-0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55-0.83) and a specificity value of 0.83 (95% CI, 0.67-0.93).ConclusionsWe found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures.Clinical trial registrationClinicalTrials.gov identifier: NCT00790543.

Increased sympathetic nervous system activity is a hallmark of hypertension (HTN), and it is implicated in altered immune system responses in its pathophysiology. However, the precise mechanisms of neural-immune interaction in HTN remain elusive. We have previously shown an association between elevated sympathetic drive to the bone marrow (BM) and activated BM immune cells in rodent models of HTN. Moreover, microglial-dependent neuroinflammation is also seen in rodent models of HTN. However, the cause-effect relationship between central and systemic inflammatory responses and the sympathetic drive remains unknown. These observations led us to hypothesize that increase in the femoral BM sympathetic nerve activity (fSNA) initiates a cascade of events leading to increase in blood pressure (BP). Here, we investigated the temporal relationship between the BM sympathetic drive, activation of the central and peripheral immune system, and increase in BP in the events leading to established HTN. The present study demonstrates that central infusion of angiotensin II (ANG II) induces early microglial activation in the paraventricular nucleus of hypothalamus, which preceded increase in the fSNA. In turn, activation of fSNA correlated with the timing of increased production and release of CD4+.IL17+T cells and other proinflammatory cells into circulation and elevation in BP, whereas infiltration of CD4+cells to the paraventricular nucleus marked establishment of ANG II HTN. This study identifies cellular and molecular mechanisms involved in neural-immune interactions in early and established stages of rodent ANG II HTN.NEW & NOTEWORTHY Early microglia activation in paraventricular nucleus precedes sympathetic activation of the bone marrow. This leads to increased bone marrow immune cells and their release into circulation and an increase in blood pressure. Infiltration of CD4+ T cells into paraventricular nucleus paraventricular nucleus marks late hypertension.

In February 2019, the U.S. Department of Health and Human Services proposed a strategic initiative to end the human immunodeficiency (HIV) epidemic in the United States by reducing new HIV infections by 90% during 2020-2030* (1). Phase 1 of the Ending the HIV Epidemic initiative focuses on Washington, DC; San Juan, Puerto Rico; and 48 counties where the majority of new diagnoses of HIV infection in 2016 and 2017 were concentrated and on seven states with a disproportionate occurrence of HIV in rural areas relative to other states.† One of the four pillars in the initiative is protecting persons at risk for HIV infection using proven, comprehensive prevention approaches and treatments, such as HIV preexposure prophylaxis (PrEP), which is the use of antiretroviral medications that have proven effective at preventing infection among persons at risk for acquiring HIV. In 2014, CDC released clinical PrEP guidelines to health care providers (2) and intensified efforts to raise awareness and increase the use of PrEP among persons at risk for infection, including gay, bisexual, and other men who have sex with men (MSM), a group that accounted for an estimated 68% of new HIV infections in 2016 (3). Data from CDC's National HIV Behavioral Surveillance (NHBS) were collected in 20 U.S. urban areas in 2014 and 2017, covering 26 of the geographic areas included in Phase I of the Ending the HIV Epidemic initiative, and were compared to assess changes in PrEP awareness and use among MSM. From 2014 to 2017, PrEP awareness increased by 50% overall, with >80% of MSM in 17 of the 20 urban areas reporting PrEP awareness in 2017. Among MSM with likely indications for PrEP (e.g., sexual risk behaviors or recent bacterial sexually transmitted infection [STI]), use of PrEP increased by approximately 500% from 6% to 35%, with significant increases observed in all urban areas and in almost all demographic subgroups. Despite this progress, PrEP use among MSM, especially among black and Hispanic MSM, remains low. Continued efforts to improve coverage are needed to reach the goal of 90% reduction in HIV incidence by 2030. In addition to developing new ways of connecting black and Hispanic MSM to health care providers through demonstration projects, CDC has developed resources and tools such as the Prescribe HIV Prevention program to enable health care providers to integrate PrEP into their clinical care.§ By routinely testing their patients for HIV, assessing HIV-negative patients for risk behaviors, and prescribing PrEP as needed, health care providers can play a critical role in this effort.

Subtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders.Single-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (50% improvement in fecal calprotectin) and maintenance concentrations ≥5 μg/mL were secondary outcomes.We enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5 μg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8 μg/mL (19.5-40) and 14 μg/mL (8.3-24) compared to 18.8 μg/mL (9.1-23, P 0.001) and 7.8 μg/mL (4-13.2, P 0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9 μg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18 μg/mL was associated with a start of maintenance concentration5 μg/mL (AUC 0.85). Independent predictors for infusion 3 levels18 μg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level29 μg/mL.We found that infusion 2 (≥29 μg/mL) and infusion 3 (≥18 μg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.

A 4-year-old boy presented with perianal abscess and granulomatous colitis, which led the diagnosis of Crohn’s disease. He became refractory to all available therapies and required colectomy. Targeted sequencing revealed a deleterious variant in NCF4, causing severe neutrophil dysfunction. He underwent hematopoietic stem cell transplantation (HSCT) with an excellent outcome.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an “age-suppressing” hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.

Background/objectives Acute pancreatitis (AP) is emerging in pediatrics. A subset of children with AP progresses to acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). The role of extensive gene testing in the progression has not been investigated previously. We have followed children enrolled in the registry and at our center for progression to ARP and CP after the first attack. Methods This study utilizes an extensive gene sequencing panel as a platform to evaluate the role of genetics in first attack AP, and the progression over time, from first attack to ARP and CP in children. Results Genes, with corresponding variants were involved in the 3 groups studied: AP, ARP and CP. We have shown that the presence of gene variants from the eight tested genes is enriched in the CP group compared to the AP and ARP groups. The presence of more than one gene was associated with CP (p = 0.01). SPINK1 mutation(s) was significantly associated with faster progression to ARP, (p = 0.04). Having a variant from CFTR, SPINK1 or PRSS1, was associated with the faster progression from AP to CP over time (p Conclusions This study shows that genetics have a significant role in progression to ARP and CP from the first attack of pancreatitis.

Background Viral infections have been suggested as possible triggers for the onset of ulcerative colitis (UC). Methods We employed VirCapSeq-Vert, a high-throughput sequencing virus capture platform, to examine the stool virome of children with newly diagnosed moderate to severe UC. We surveyed fecal samples collected at presentation, after symptom remission, and from a control group diagnosed with irritable bowel syndrome. Results Seventy subjects with UC (mean age 13 years, 45 had moderate symptoms, 25 had severe, 69 of 70 had a Mayo endoscopy subscore 2/3) were studied. We detected a wide range of animal viruses that were taxonomically classified into 12 viral families. A virus was present in 50% of fecal samples collected at presentation, 41% of samples collected after remission, and 40% of samples in our control group. The most frequently identified viruses were diet-based gyroviruses. The UC cohort had a significantly higher prevalence of anelloviruses compared with the control cohort. However, we did not identify a single virus that can be implicated in the onset of UC and did not find an association between UC disease severity and viral presence. Conclusion Presence of virus in stool was not associated with the onset of pediatric UC., We used VirCapSeq-VERT, a high-throughput sequencing virus capture platform, to examine the stool virome of children with newly diagnosed moderate to severe ulcerative colitis. We did not identify a link between a viral infection and the onset of ulcerative colitis.

To examine human mandibular angle integrity alterations accompanying a mandibular body block graft harvest surgical procedure.Hemimandibles from 24 human cadavers were resected and sorted into one of three groups by residual dental status. The height of each hemimandible body was obtained and recorded. Acrylic bone cement was utilized to mount the hemimandibles at the mandibular condyle. Using standard surgical instruments and techniques, cortical bone of the mandibular body buccal plate was resected from the right hemimandibles. Left hemimandibles were used as a control. Each hemimandible was secured in an Instron 5565 mechanical unit. With forces placed on and perpendicular to the occlusal plane, each hemimandible underwent sequential loading until osseous fracture occurred. Descriptive statistics between grouped data were compared and discussed in terms of mean, minimum, and maximum. The statistical relationship between the maximal load, gender, and mandibular body height were identified.Donor and control hemimandible maximal load mean values were 423.63 N and 957.90 N, respectively. A statistically significant difference was present between maximal loads of donor and control hemimandibles (P.0001). Correlations of statistical significance were present between mandibular bone height and maximal load in the control hemimandibles (P = .009). Correlations of statistical significance were not found between mandibular bone height, displacement at maximal load, and maximal load in the grafted hemimandibles (P.05). No statistically significant correlation between dental status and gender was found in the donor and control hemimandibles (P.05).After subjected to a typical block graft harvest surgical procedure, the human mandible's integrity is significantly altered. Gender, dental status, and mandibular bone height do not correlate with maximal load,and thus integrity, of donor and control mandibles.

Avoiding fibrostenotic complications is of paramount concern in the management of Crohn's disease (CD). We sought to investigate the association of candidate biomarkers of fibrosis collected at diagnosis with the future development of fibrostenotic CD.Using the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort, a multicenter prospective observational pediatric inception cohort, subjects with an inflammatory phenotype (B1) at diagnosis who later converted to a stricturing phenotype (B2) within 3 years were compared with those who remained B1. Serum collected at diagnosis underwent both parallel reaction monitoring-targeted proteomic analysis and conventional enzyme-linked immunosorbent assay for 10 candidate biomarkers of intestinal fibrosis. Cox proportional hazard regression was used for multivariable analysis of time-dependent outcomes.In 116 subjects 58 subjects with verified B1 phenotype at diagnosis who later converted to B2 disease were compared with 58 subjects who remained B1 over 3 years of follow-up. Extracellular matrix protein 1 (ECM1) levels in the upper quartile (hazard ratio [HR] 3.43, 95% confidence limit [CL] 1.33, 8.42) were associated with future fibrostenotic disease. ASCA IgA (HR 4.99, 95% CL 1.50, 16.68) and CBir levels (HR 5.19, 95% CL 1.83, 14.74) were also associated with future intestinal fibrostenosis, although ECM1 continued to demonstrate independent association with conversion to B2 even with adjustment for serologies in multivariable analysis (HR 5.33, 95% CL 1.29, 22.13).ECM1 and other biomarkers of fibrosis may aid in determining the risk of uncomplicated inflammatory disease converting to B2 stricturing phenotypes in children with CD. Prospective validation studies to verify test performance and optimize clinical utilization are needed before clinical implementation.

Asthma is a common disorder that affects genders differently across the life span. Earlier in life, it is more common in boys. At puberty, asthma becomes more common and often more severe in girls and women. The effect of sex hormones on asthma incidence and its severity is difficult to differentiate from other asthma severity risk factors, such as racial background, socioeconomic factors, obesity, atopy, environmental exposure, and, in particular, lung aging. Recognizing gender-associated and age-associated differences is important to understanding the pathobiology of asthma and to providing effective education and personalized care for patients with asthma across the life course.

Background As part of a multicomponent delirium prevention protocol the Confusion Assessment Method (Short-CAM) was introduced to nursing as the standard delirium screening instrument on the general medical units. Despite significant educational efforts, quality monitoring revealed poor sensitivity with the use of Short-CAM. Objectives To compare the validity of the Nursing Delirium Screening Scale (Nu-DESC) and Short-CAM on general medical units and to explore the impact of delirium education on the successful implementation of delirium screening tools. Methods In this quality improvement project, both Nu-DESC and Short-CAM were scored by nurses on 2 general medical units, per standard practice. Two blinded physician-raters determined delirium diagnosis in 192 patients on these units on 8 separate days, utilizing the Diagnostic and Statistical Manual of Mental Disorders-5 criteria as the reference standard. Sensitivity and specificity of both scales were calculated. Results Thirty-five of 192 patients (18.2%) were suffering from delirium on the day of assessment. The Short-CAM scored positive for 3 (1.6%) patients and the Nu-DESC for 50 (26.0%) patients on the same day as the physician-raters assessment. Sensitivity and specificity were respectively calculated at 8.6% and 100% for the Short-CAM and 77.1% and 85.4% for the Nu-DESC. There was no statistical difference in sensitivity and specificity of the Nu-DESC on the units regardless of the level of preimplementation delirium education. Conclusions The Nu-DESC was shown to be an easy-to-deploy delirium-screening tool on general medical units with improved sensitivity when compared to the Short-CAM.

Ketamine is currently being used as an anesthetic/antiepileptic drug in refractory status epilepticus. To validate its use, 2 clinical trials are recruiting patients. However, preclinical studies of its use in chemically induced status epilepticus in rodents have shown that it is remarkably neuroprotective, through N-methyl-d-aspartate-receptor blockade, even when given after the onset of status epilepticus. Human studies have shown that status epilepticus-induced brain damage can be caused by a glutamate analogue and that it occurs in the same brain regions as in the animal studies. We therefore propose that ketamine be started early in the course of human status epilepticus as a neuroprotectant and that it be continued until epileptic discharges are eliminated. Using it as an anesthetic/antiepileptic drug late in the course of refractory status epilepticus only ensures that it is given after widespread brain damage has occurred.